Melanoma is the most deadly form of human skin cancer. It is estimated that one American dies from melanoma every hour. However, melanoma is a highly curable disease when detected at early stages. Determining the etiology of melanoma and the early mechanisms involved in its development will permit earlier detection and design of more effective drugs to treat it and prevent its reoccurrence. The long-range goal of this research is to identify the early molecular events responsible for the development of malignant melanoma. Sunlight ultraviolet radiation (UV) is the prominent environmental carcinogen known to be involved in melanoma. The UVA wavelengths (320-400 nm) of the solar spectrum now seem to play a much more important role in melanoma than previous thought. The primary objective of this proposal is to determine if UVA irradiation of melanocyte stem cells increases the incidence of melanocyte tumors in the adult. The central hypothesis is that the more penetrating UVA radiation reaches the dermal layer of the skin and causes mutations in the melanocyte stem cell or in its transit amplifying cells thereby contributing to the early stages of melanoma. This project will use a recently discovered method in zebra fish for eliminating adult melanophores and synchronizing melanocyte regeneration from melanocyte stem cells to determine if UVA irradiation of melanocyte stem cells will increase the incidence of melanocytic tumors. The transgenic zebra fish model for human melanoma which has the human BRAF founder mutation for melanoma will be used to accomplish the following specific aims: (1) determine if UVA irradiation of melanocyte stem cells will increase the incidence of melanocyte proliferations in nevi (moles) and the development of melanoma, and whether additional UVA irradiation of the regenerated adult melanocytes derived from these irradiated stem cells will increase the incidence melanoma, and (2) determine if cellular senescence, known to be a powerful tumor-suppressive process that prevents excessive proliferation, is suppressed in nevi or tumors by UVA irradiation of either melanocyte stem cells or adult melanocytes. The results of this research will help to unravel the early mechanisms that contribute to the development of melanoma, and determine if UVA radiation of melanocyte stem cells plays an important role in this process. PUBLIC HEALTH RELEVANCE: This research project will help determine how exposure to sunlight and artificial sources of sunlight such as tanning and phototherapeutic devices contribute to the early events in the development of melanoma. It will determine if exposure to the UVA wavelengths will mutate melanocyte stem cells and contribute to the development of melanoma. Understanding the early events in melanoma will permit earlier detection and development of more effective drugs to treat it and prevent it reoccurrence.